Astrocytes exploit a neutrophil extracellular trap - like mechanism for myelin management: A new perspective on myelin-related disorders.

The canonical innate immune functions of astrocytes play a critical role in maintaining CNS homeostasis, including myelin remodeling - a physiological process that unfolds throughout life. Elimination of aged myelin and myelin debris is necessary to support remyelination. Myelin debris are cleared by professional CNS phagocytes microglial cells by classical phagocytosis mechanism and by non-professional phagocytes astrocytes through a mechanism which is not yet fully understood. Here, we demonstrate for the first time that, to process myelin, primary astrocytes from the mouse brain engage a specific innate immune mechanism that was previously unrecognized in these cells. This mechanism, resembling neutrophil extracellular traps (NET), we termed AsET (Astrocyte Extracellular Trap), shares morphological, kinetic, and molecular characteristics with non-suicidal NETs as demonstrated by transmission and scanning electron microscopy, immunocytochemistry, immunohistochemistry, and Western blot analyses. The main molecular NET/AsET marker citrullinated histone H3 (H3Cit) protein is present in brain cortex and striatum sections from normal mice in association with astrocytes and significantly increases in Huntington disease (HD) R6/1 mice with myelination defect. We propose that AsET is part of a normal physiological process of astrocyte-mediated myelin remodeling in the healthy brain, which can be over-activated under myelin-related disorders and contributes to neuroinflammation.